Over the last 15 years, the PI's effort to investigate the 'immune and non-immune mechanisms of renal diseases' has progressively focused on the role of the renin-angiotensin system (RAS). Through animal and human studies, the PT has documented that angiotensin II produces damages to the kidney through several previously recognized and unrecognized biological properties. In an attempt to pinpoint the specific biological events involved in the actions of angiotensin II, the PI took the step to completely and selectively inactivate the several genes comprising RAS, i.e., the genes of its precursor, metabolizing enzyme and receptors. From the early stage of analyzing the produced mutants, however, the PI began to realize that RAS has an important physiological role for the ontogeny of the kidney and urinary tract, and that, in fact, a defect in this system, can cause diseases of the kidney and urinary tract. A mutation in one of those genes has even been linked to a special group of common (1 / 100 births) congenital human diseases, which are collectively called 'congenital anomalies of the kidney and urinary tract'. Taking this newly arrived opportunity, the PI now plans to delineate the ontogeny of this disease entity, and at the same time, to shed light into the physiologic role of RAS in normal kidney and urinary tract development.